VEGFR-2 and VEGFR-3 inhibitory anthranilamide pyridones

ABSTRACT

Novel VEGFR-2 and VEGFR-3 inhibitory anthranilamide pyridones and their use as pharmaceutical agents for treating diseases that are triggered by persistent angiogenesis are selected.

This application claims the benefit of the filing date of U.S.Provisional Application Ser. No. 60/482,009 filed Jun. 25, 2003.

The invention relates to VEGFR-2 and VEGFR-3 inhibitory anthranilamidepyridones and their use as pharmaceutical agents for treating diseasesthat are triggered by persistent angiogenesis.

Persistent angiogenesis can be the cause or precondition of variousdiseases, such as tumor or metastasis growth, psoriasis; arthritis, suchas rheumatoid arthritis, hemangioma, angiofibroma; eye diseases, such asdiabetic retinopathy, neovascular glaucoma; renal diseases, such asglomerulonephritis, diabetic nephropathy, malignant nephrosclerosis,thrombic microangiopathic syndrome, transplant rejections andglomerulopathy; fibrotic diseases, such as cirrhosis of the liver,mesangial cell proliferative diseases and arteriosclerosis, or canresult in an aggravation of these diseases.

Persistent angiogenesis is induced by the factor VEGF via its receptor.So that VEGF can exert this action, it is necessary that VEGF bind tothe receptor, and a tyrosine phosphorylation is induced.

Direct or indirect inhibition of the VEGF receptor (VEGF=vascularendothelial growth factor) can be used for treating such diseases andother VEGF-induced pathological angiogenesis and vascular permeableconditions, such as tumor vascularization. For example, it is known thatthe growth of tumors can be inhibited by soluble receptors andantibodies against VEGF.

Anthranilamide pyridonamides that are used as pharmaceutical agents fortreating psoriasis; arthritis, such as rheumatoid arthritis, hemangioma,angiofibroma; eye diseases, such as diabetic retinopathy, neovascularglaucoma; renal diseases, such as glomerulonephritis, diabeticnephropathy, malignant nephrosclerosis, thrombic microangiopathicsyndrome, transplant rejections and glomerulopathy; fibrotic diseases,such as cirrhosis of the liver, mesangial cell proliferative diseases,arteriosclerosis, injuries to nerve tissue, and for inhibiting thereocclusion of vessels after balloon catheter treatment, in vascularprosthetics or after mechanical devices are used to keep vessels open,such as, e.g., stents, are known from WO 00/27820 (e.g., Example 38).

The compounds that are known from WO 00/27820 are generally effective inthe indications cited, but their effectiveness is not very pronounced.

Anthranilic acid amides that are highly effective but also exhibit goodinhibition of the Cytochrome P 450 isoenzyme 3A4 are also known from WO03/040102. The Cytochrome P 450 isoenzyme 3A4 is one of the essentialmetabolic enzymes via which pharmaceutical agents are degraded. Aninhibition of this isoenzyme results in undesirable pharmaceutical agentinteractions, especially in the case of multimorbid patients (patientswith multiple disease conditions). There also exists the problem that ina combination therapy with other medications, increased toxicity occurs,which results from the inhibition of the degradation of the compoundsand the associated excessive serum levels.

There is therefore the desire for active ingredients that on the onehand are effective and on the other hand are more compatible or do notexhibit any undesirable side effects.

It has now been found that compounds of general formula I

in which

-   -   A stands for an aryl or heteroaryl,    -   X stands for hydrogen or fluorine,    -   R¹ and R², independently of one another, stand for hydrogen,        halogen, C₁-C₁₂-alkyl, C₁-C₁₂-alkoxy-C₁-C₁₀-alkylene,        halo-C₁-C₁₀-alkyl, C₃-C₁₀-cycloalkyl or halo-C₃-C₁₀-cycloalkyl,        and    -   Y stands for a bond or for oxygen or for the group —S—, —S(O)—        or —SO₂—, as well as isomers, enantiomers, diastereomers and        salts thereof,        overcome the above-indicated drawbacks.

Alkyl is defined in each case as a straight-chain or branched alkylradical, such as, for example, methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, pentyl, isopentyl or hexyl, heptyl, octyl, nonyl,decyl, undecyl, or dodecyl.

Alkoxy is defined in each case as a straight-chain or branched alkoxyradical, such as, for example, methyloxy, ethyloxy, propyloxy,isopropyloxy, butyloxy, isobutyloxy, sec-butyloxy, pentyloxy,isopentyloxy, hexyloxy, heptyloxy, octyloxy, nonyloxy, decyloxy,undecyloxy or dodecyloxy.

Cycloalkyls are defined as monocyclic alkyl rings, such as cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, cyclooctyl,cyclononyl or cyclodecyl, but also bicyclic rings or tricyclic rings,such as, for example, adamantanyl.

Cycloalkyl radicals can contain, instead of the carbon atoms, one ormore heteroatoms, such as oxygen, sulfur and/or nitrogen. Thoseheterocycloalkyls with 3 to 8 ring atoms are preferred.

Halogen is defined in each case as fluorine, chlorine, bromine oriodine.

Haloalkyl is defined as an alkyl radical, which can be substituted inone or more places with halogen.

The aryl radical in each case comprises 3-12 carbon atoms and can ineach case be benzocondensed.

For example, there can be mentioned: cyclopropenyl, cyclopentadienyl,phenyl, tropyl, cyclooctadienyl, indenyl, naphthyl, azulenyl, biphenyl,fluorenyl, anthracenyl, etc.

The heteroaryl radical in each case comprises 3-16 ring atoms, andinstead of the carbon can contain one or more heteroatoms that are thesame or different, such as oxygen, nitrogen or sulfur, in the ring, andcan be monocyclic, bicyclic, or tricyclic, and in addition in each casecan be benzocondensed.

For example, there can be mentioned:

Thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl,isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, etc.,and benzo derivatives thereof, such as, e.g., benzofuranyl,benzothienyl, benzoxazolyl, benzimidazolyl, indazolyl, indolyl,isoindolyl, etc.; or pyridyl, pyridazinyl, pyimidinyl, pyrazinyl,triazinyl, etc., and benzo derivatives thereof, such as, e.g., quinolyl,isoquinolyl, etc.; or azocinyl, indolizinyl, purinyl, etc., and benzoderivatives thereof; or quinolinyl, isoquinolinyl, cinnolinyl,phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl,carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl,xanthenyl, or oxepinyl, etc.

If an acid group is included, the physiologically compatible salts oforganic and inorganic bases are suitable as salts, such as, for example,the readily soluble alkali salts and alkaline-earth salts as well asN-methyl-glucamine, dimethyl-glucamine, ethyl-glucamine, lysine,1,6-hexadiamine, ethanolamine, glucosamine, sarcosine, serinol,tris-hydroxy-methyl-amino-methane, aminopropanediol, Sovak base, and1-amino-2,3,4-butanetriol.

If a basic group is included, the physiologically compatible salts oforganic and inorganic acids are suitable, such as hydrochloric acid,sulfuric acid, phosphoric acid, citric acid, tartaric acid, fumaricacid, i.a.

Those compounds of general formula I in which

-   -   A stands for a phenyl or pyridyl,    -   X stands for hydrogen or fluorine,    -   R¹ and R², independently of one another, stand for hydrogen,        halogen, C₁-C₁₂-alkyl, C₁-C₁₂-alkoxy-C₁-C₁₀-alkylene,        halo-C₁-C₁₀-alkyl, C₃-C₁₀-cycloalkyl or halo-C₃-C₁₀-cycloalkyl        and    -   Y stands for a bond or for oxygen or for the group —S—, —S(O)—        or —SO₂—, as well as isomers, enantiomers, diastereomer and        salts thereof,        have special properties.

Those compounds of general formula I in which

-   -   A stands for a phenyl,    -   X stands for hydrogen or fluorine,    -   R¹ and R², independently of one another, stand for hydrogen,        halogen, C₁-C₁₂-alkyl, C₁-C₁₂-alkoxy-C₁-C₁₀-alkylene,        halo-C₁-C₁₀-alkyl, C₃-C₁₀-cycloalkyl or halo-C₃-C₁₀-cycloalkyl,        and    -   Y stands for a bond or for oxygen or for the group —S—, —S(O)—        or —SO₂—, as well as isomers, enantiomers, diastereomers, and        salts thereof,        are especially advantageous.

Those compounds of general formula I in which

-   -   A stands for a phenyl,    -   X stands for hydrogen,    -   R¹ and R², independently of one another, stand for hydrogen,        halogen, C₁-C₁₂-alkyl, C₁-C₁₂-alkoxy-C₁-C₁₀-alkylene,        halo-C₁-C₁₀-alkyl, C₃-C₁₀-cycloalkyl or halo-C₃-C₁₀-cycloalkyl,        and    -   Y stands for a bond or for oxygen or for the group —S—, —S(O)—        or —SO₂—, as well as isomers, enantiomers, diastereomers, and        salts thereof,        are preferred.

The compounds of general formula I according to the invention alsocontain the possible tautomeric forms and comprise the E- or Z-isomersor, if a chiral center is present, also the racemates and enantiomers.

The compounds of formula I as well as their physiologically compatiblesalts can be used as pharmaceutical agents based on their inhibitoryactivity relative to the phosphorylation of the VEGF receptor. Based ontheir profile of action, the compounds according to the invention aresuitable for treating diseases that are caused or promoted by persistentangiogenesis.

Since the compounds of formula I are identified as inhibitors of thetyrosine kinases KDR, FLT-1 and FLT-4, they are suitable in particularfor treating those diseases that are caused or promoted by persistentangiogenesis that is triggered via the VEGF receptor or by an increasein vascular permeability.

The subject of this invention is also the use of the compounds accordingto the invention as inhibitors of the tyrosine kinases KDR, FLT-1 andFLT-4.

Subjects of this invention are thus also pharmaceutical agents fortreating tumors or use thereof.

The compounds according to the invention can be used either alone or ina formulation as pharmaceutical agents for treating tumor or metastasisgrowth, psoriasis, Kaposi's sarcoma, restenosis, such as, e.g.,stent-induced restenosis, endometriosis, Crohn's disease, Hodgkin'sdisease, leukemia; arthritis, such as rheumatoid arthritis, hemangioma,angiofibroma; eye diseases, such as diabetic retinopathy, neovascularglaucoma; renal diseases, such as glomerulonephritis, diabeticnephropathy, malignant nephrosclerosis, thrombic microangiopathicsyndrome, transplant rejections and glomerulopathy; fibrotic diseases,such as cirrhosis of the liver, mesangial cell proliferative diseases,arteriosclerosis, injuries to nerve tissue, and for inhibiting thereocclusion of vessels after balloon catheter treatment, in vascularprosthetics or after mechanical devices are used to keep vessels open,such as, e.g., stents, as immunosuppressive agents, for supportingscar-free healing, in senile keratosis and in contact dermatitis.

In treating injuries to nerve tissue, quick scar formation on the injurysites can be prevented with the compounds according to the invention,i.e., scar formation is prevented from occurring before the axonsreconnect. A reconstruction of the nerve compounds would thus befacilitated.

The formation of ascites in patients can also be suppressed with thecompounds according to the invention. VEGF-induced edemas can also besuppressed.

Lymphangiogenesis plays an important role in lymphogenic metastasizing(Karpanen, T. et al., Cancere Res. 2001 March 1, 61(5): 1786-90,Veikkola, T., et al., EMBO J. 2001, March 15; 20 (6): 1223-31).

The compounds according to the invention now also show excellent actionas VEGFR kinase 3 inhibitors and are therefore also suitable aseffective inhibitors of lymphangiogenesis.

By a treatment with the compounds according to the invention, not only areduction of the size of metastases but also a reduction of the numberof metastases is achieved.

Such pharmaceutical agents, their formulations and uses are alsosubjects of this invention.

The invention thus also relates to the use of the compounds of generalformula I for the production of a pharmaceutical agent for use as or fortreatment of psoriasis, Kaposi's sarcoma, restenosis, such as, e.g.,stent-induced restenosis, endometriosis, Crohn's disease, Hodgkin'sdisease, leukemia; arthritis, such as rheumatoid arthritis, hemangioma,angiofibroma; eye diseases, such as diabetic retinopathy, neovascularglaucoma; renal diseases, such as glomerulonephritis, diabeticnephropathy, malignant nephrosclerosis, thrombic microangiopathicsyndrome, transplant rejections and glomerulopathy; fibrotic diseases,such as cirrhosis of the liver, mesangial cell proliferative diseases,arteriosclerosis, injuries to nerve tissue, and for inhibiting thereocclusion of vessels after balloon catheter treatment, in vascularprosthetics or after mechanical devices are used to keep vessels open,such as, e.g., stents, as inmunosuppressive agents, as a support inscar-free healing, in senile keratosis and in contact dermatitis.

The formation of ascites in patients can also be suppressed with thecompounds according to the invention. VEGF-induced edemas can also besuppressed.

To use the compounds of formula I as pharmaceutical agents, the latterare brought into the form of a pharmaceutical preparation, which inaddition to the active ingredient for enteral or parenteraladministration contains suitable pharmaceutical, organic or inorganicinert carrier materials, such as, for example, water, gelatin, gumarabic, lactose, starch, magnesium stearate, talc, vegetable oils,polyalkylene glycols, etc. The pharmaceutical preparations can bepresent in solid form, for example as tablets, coated tablets,suppositories, or capsules, or in liquid form, for example as solutions,suspensions or emulsions. They optionally contain, moreover, adjuvantssuch as preservatives, stabilizers, wetting agents or emulsifiers, saltsfor changing osmotic pressure or buffers.

For parenteral administration, especially injection solutions orsuspensions, especially aqueous solutions of the active compounds inpolyhydroxyethoxylated castor oil, are suitable.

As carrier systems, surface-active adjuvants such as salts of bile acidsor animal or plant phospholipids, but also mixtures thereof as well asliposomes or components thereof can also be used.

For oral administration, especially tablets, coated tablets or capsuleswith talc and/or hydrocarbon vehicles or binders, such as for example,lactose, corn starch or potato starch, are suitable. The administrationcan also be carried out in liquid form, such as, for example, as juice,to which optionally a sweetener or, if necessary, one or more flavoringsubstances, is added.

The dosage of the active ingredients can vary depending on the method ofadministration, age and weight of the patient, type and severity of thedisease to be treated and similar factors. The daily dose is 0.5-1000mg, preferably 50-200 mg, whereby the dose can be given as a single doseto be administered once or divided into 2 or more daily doses.

The above-described formulations and forms for dispensing are alsosubjects of this invention.

The production of the compounds according to the invention is carriedout according to methods that are known in the art. For example,compounds of general formula I are obtained in that a compound ofgeneral formula II

in which X has the meaning that is indicated in general formula I andR^(x) stands for hydrogen or C₁-C₆-alkyl, is first subjected toreductive amination to obtain a compound of general formula (III)

and then is converted into the corresponding amide of general formula I,and then optionally compounds of general formula I are oxidized to asulfur compound. The sequence of the steps can also be exchanged,whereby Rx preferably stands for C₁-C₆-alkyl. If R^(x) stands forC₁-C₆-alkyl, it can also optionally first be saponified and thenconverted into the corresponding amide.

The reductive amination is carried out with aldehydes or ketones,whereby the reaction is performed in the presence of a reducing agent,such as, for example, sodium cyanoborohydride in a suitable inertsolvent, such as, for example, ethanol, at temperatures of 0° C. up tothe boiling point of the solvent. An addition of acids, such as glacialacetic acid, can also prove advantageous. This reaction sequence can beperformed as a single-pot process. It can prove advantageous to isolatethe amine that is first produced and then in a separate step to reduceit, for example, with sodium borohydride in solvents such asacetonitrile.

The amide formation is carried out according to methods that are knownin the literature.

For amide formation, it is possible to start from a corresponding ester.The ester is reacted according to J. Org. Chem. 1995, 8414 with aluminumtrimethyl and the corresponding amine in solvents such as toluene attemperatures of 0° C. to the boiling point of the solvent. If themolecule contains two ester groups, both are converted into the sameamide. Instead of aluminum trimethyl, sodium hexamethyldisilazide canalso be used.

For amide formation, however, all processes that are known from peptidechemistry are also available. For example, the corresponding acid can bereacted with the amine in aprotic polar solvents, such as, for example,dimethylformamide, via an activated acid derivative that can beobtained, for example, with hydroxybenzotriazole and a carbodiimide,such as, for example, diisopropylcarbodiimide, at temperatures ofbetween 0° C. and the boiling point of the solvent, preferably at 80° C.The reaction between carboxylic acid and amine, however, can also beproduced by activation reagents such as HATU(N-dimethylamino-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminiumhexafluorophosphate-N-oxide), whereby polar aprotic solvents, such as,for example, dimethylformamide, are suitable for the reaction. Theaddition of a base such as N-methylmorpholine is necessary. The reactionproceeds at temperatures of 0-100° C., whereby the procedure ispreferably performed at room temperature. For the amide formation, theprocess can also be used with the acid halide, the mixed acid anhydride,imidazolide or azide. A previous protection of an additional aminogroup, for example as an amide, is not necessary in all cases, but canadvantageously influence the reaction.

The oxidation of sulfur is carried out according to methods that areknown in the literature. The sulfur compound can thus be reacted withoxidizing agents, such as m-chloroperbenzoic acid, in solvents, such asdichloromethane, whereby a mixture of sulfoxide and sulfone can beobtained. Hydrogen peroxide can also be used as an oxidizing agent insolvents, such as, for example, glacial acetic acid. Also, an oxidationwith sodium periodate in the presence of ruthenium trichloride, insolvents such as acetonitrile with carbon tetrachloride or sodiumperiodate in methanol with water, is possible, whereby in the formermethod, the sulfone is produced and in the latter method, primarily thesulfoxide is produced.

Production of the Compounds According to the Invention

The following examples explain the production of the compounds accordingto the invention without the scope of the claimed compounds beinglimited to these examples.

EXAMPLE 1

2-[(6-Oxo-1,6-dihydro-pyridin-3-ylmethyl)-amino]-N-(4-trifluoromethoxy-phenyl)-benzamide

441 mg (1.8 mmol) of2-[(6-oxo-1,6-dihydro-pyridin-3-ylmethyl)-amino]-benzoic acid isintroduced into 12 ml of methylene chloride in a moisture-freeenvironment and under argon and mixed in succession with 456 mg (4.5mmol) of N-methylmorpholine and 336 mg of 4-trifluoromethoxyaniline and822 mg (2.16 mmol) of HATU(N-dimethylamino-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminiumhexafluorophosphate-N-oxide, and it is stirred for 2.5 hours at roomtemperature. The acid goes into solution. Then, it is heated for 1.5hours to a bath temperature of 100° C. First, a product precipitates,which then goes into solution again. It is concentrated by evaporationin a vacuum, and the residue is dispersed into dilute sodium bicarbonatesolution and ethyl acetate. The organic phase is washed, dried, filteredand concentrated by evaporation. The residue is chromatographed on 10 gof silica gel (Isolute, flash, SI) with a gradient of CH₂Cl₂ onCH₂Cl₂:MeOH=9:1 as an eluant, and 414 mg of a product is obtained thatis absorptively precipitated with methylene chloride:diisopropylether=5:1, and after suctioning off, 364 mg (50.1% of theory) of2-[(6-oxo-1,6-dihydro-pyridin-3-ylmethyl)-amino]-N-(4-trifluoromethoxy-phenyl)-benzamidewith a melting point of 189.2° C. is produced.

Similarly produced are also:

Example

Molecular Weight Melting Point (° C.) or Molar Peak m/e 1.1

34939 150.6 1.2

377.44 Resin 1.3

363.42 172.2 1.4

405.50 159 1.5

417.39 1.6

335.36 1.7

403.36 1.8

419.43 1.9

419.43 1.10

393.44 111.2 1.11

417.39 191 1.12

385.37 178.8 1.13

379.41 1.14

385.37 1.15

385.37 110.6 1.16

349.39 1.17

377.44 1.18

431.42 1.19

467.40 1.20

485.39 1.21

513.44 1.22

383.84 1.23

391.30Production of the Starting Materials:

2-[(6-Oxo-1,6-dihydro-pyridin-3-ylmethyl)-amino]-benzoic Acid a.)2-[(6-Oxo-1,6-dihydro-pyridin-3-ylmethyl)-amino]-benzoic Acid MethylEster

4.53 g (30 mmol) of anthranilic acid methyl ester is mixed in 209 ml ofmethanol with 2.09 ml of glacial acetic acid and 5.76 g (42 mmol) of2-pyridone5-carbaldehyde, and it is stirred for 24 hours at roomtemperature under argon and in a moisture-free environment. It is thenmixed in portions with 2.64 g (42 mmol) of sodium cyanoborohydride, andit is stirred for 3 days at room temperature. It is then evaporated tothe dry state in a vacuum, taken up in 150 ml of dilute sodiumbicarbonate solution, absorptively precipitated and suctioned off. As aresidue, 4.75 g (61% of theory) of2-[(6-oxo-1,6-dihydro-pyridin-3-ylmethyl)-amino]-benzoic acid methylester is obtained.

b.) 2-[(6-Oxo-1,6-dihydro-pyridin-3-ylmethyl)-amino]-benzoic Acid

3.5 g (12.7 mmol) of2-[(6-oxo-1,6-dihydro-pyridin-3-ylmethyl)-amino]-benzoic acid-methylester is mixed in 15 ml of dimethylformamide with 30 ml of 6N sodiumhydroxide solution and stirred for 1.5 hours at room temperature. Whilebeing cooled with ice, it is then mixed with about 50 ml of 4Nhydrochloric acid, the precipitation is suctioned off, and it is washedwith water. 3.1 g, which is taken up in 29.3 ml of 1N sodium hydroxidesolution and 142 ml of ethanol, is obtained, and it is heated for 1.5hours to a bath temperature of 120° C. The ethanol is then drawn off ina vacuum, it is made acidic with 2N hydrochloric acid, and theprecipitated product is suctioned off and dried well. 2.9 g (93.5% oftheory) of 2-[(6-oxo-1,6-dihydro-pyridin-3-ylmethyl)-amino]-benzoic acidis obtained.

The sample applications below explain the biological action and the useof the compounds according to the invention without the latter beinglimited to the examples.

Solutions Required for the Tests

Stock Solutions

-   -   Stock solution A: 3 mmol of ATP in water, pH 7.0 (−70° C.)    -   Stock solution B: g-33P-ATP 1 mCi/100 μl    -   Stock solution C: poly-(Glu4Tyr) 10 mg/ml in water

Solution for Dilutions

-   -   Substrate solvent: 10 mmol of DTT, 10 mmol of manganese        chloride, 100 mmol of magnesium chloride    -   Enzyme solution: 120 mmol of tris/HCl, pH 7.5, 10 μM of sodium        vanadium oxide        Sample Application 1        Inhibition of the KDR- and FLT-1 Kinase Activity in the Presence        of the Compounds According to the Invention

In a microtiter plate (without protein binding) that tapers to a point,10 μl of substrate mix (10 μl of volume of ATP stock solution A+25 μCiof g-33P-ATP (about 2.5 μl of stock solution B)+30 μl of poly-(Glu4Tyr)stock solution C+1.21 ml of substrate solvent), 10 μl of inhibitorsolution (substances corresponding to the dilutions, 3% DMSO insubstrate solvent as a control) and 10 μl of enzyme solution (11.25 μgof enzyme stock solution (KDR, FLT-1 or FLT-4 kinase) are added at 4° C.in 1.25 ml of enzyme solution (dilute). It is thoroughly mixed andincubated for 10 minutes at room temperature. Then, 10 μl of stopsolution (250 mmol of EDTA, pH 7.0) is added, mixed, and 10 μl of thesolution is transferred to a P 81 phosphocellulose filter. Then, it iswashed several times in 0.1 M phosphoric acid. The filter paper isdried, coated with Meltilex, and measured in a microbeta counter.

The IC50 values are determined from the inhibitor concentration, whichis necessary to inhibit the phosphate incorporation to 50% of theuninhibited incorporation after removal of the blank reading(EDTA-stopped reaction).

Sample Application 2

Cytochrome P450 Inhibition

The Cytochrome P450 inhibition was performed according to thepublication of Crespi et al. (Anal. Biochem., 248, 188-190 (1997)) withuse of the baculovirus/insect cell-expressed and human Cytochrome P 450isoenzyme (3A4).

The results of the kinase-inhibition IC50 in nM and the inhibition ofthe Cytochrome P450 isoenzyme Cyt P 3A4 (IC50, nM) are presented in thetable below: Inhibition of Cyp VEGFR II (KDR) 450 3A4 Example No. [nM][nM] Example 38 from 180 4600 WO 00/27820 Example 5 from 25 1500 WO03/040102 Example 1.0 56 5600 Example 1.5 59 11.000

The superior action of the compounds according to the invention comparedto the known compounds can be seen clearly from the results.

Without further elaboration, it is believed that one skilled in the artcan, using the preceding description, utilize the present invention toits fullest extent. The preceding preferred specific embodiments are,therefore, to be construed as merely illustrative, and not limitative ofthe remainder of the disclosure in any way whatsoever.

In the foregoing and in the examples, all temperatures are set forthuncorrected in degrees Celsius and, all parts and percentages are byweight, unless otherwise indicated.

The entire disclosures of all applications, patents and publications,cited herein and of corresponding German application No. 10327719.6,filed Jun. 13, 2002 and U.S. Provisional Application Ser. No.60/482,009, filed Jun. 25, 2003, are incorporated by reference herein.

The preceding examples can be repeated with similar success bysubstituting the generically or specifically described reactants and/oroperating conditions of this invention for those used in the precedingexamples.

From the foregoing description, one skilled in the art can easilyascertain the essential characteristics of this invention and, withoutdeparting from the spirit and scope thereof, can make various changesand modifications of the invention to adapt it to various usages andconditions.

1. Compounds of general formula I

in which A stands for an aryl or heteroaryl, X stands for hydrogen orfluorine, R¹ and R², independently of one another, stand for hydrogen,halogen, C₁-C₁₂-alkyl, C₁-C₁₂-alkoxy-C₁-C₁₀-alkylene, halo-C₁-C₁₀-alkyl,C₃-C₁₀-cycloalkyl or halo-C₃-C₁₀-cycloalkyl, and Y stands for a bond orfor oxygen or for the group —S—, —S(O)— or —SO₂—, as well as isomers,enantiomers, diastereomers and salts thereof.
 2. Compounds of generalformula I, according to claim 1, in which A stands for a phenyl orpyridyl, X stands for hydrogen or fluorine, R¹ and R², independently ofone another, stand for hydrogen, halogen, C₁-C₂-alkyl,C₁-C₁₂-alkoxy-C₁-C₁₀-alkylene, halo-C₁-C₁₀-alkyl, C₃-C₁₀-cycloalkyl orhalo-C₃-C₁₀-cycloalkyl and Y stands for a bond or for oxygen or for thegroup —S—, —S(O)— or —SO₂—, as well as isomers, enantiomers,diastereomer and salts thereof.
 3. Compounds of general formula I,according to claims 1 and 2 claim 1, in which A stands for a phenyl, Xstands for hydrogen or fluorine, R¹ and R², independently of oneanother, stand for hydrogen, halogen, C₁-C₁₂-alkyl,C₁-C₁₂-alkoxy-C₁-C₁₀-alkylene, halo-C₁-C₁₀-alkyl, C₃-C₁₀-cycloalkyl orhalo-C₃-C₁₀-cycloalkyl, and Y stands for a bond or for oxygen or for thegroup —S—, —S(O)— or —SO₂—, as well as isomers, enantiomers,diastereomers, and salts thereof.
 4. Compounds of general formula I,according to claims 1 to 3 claim 1, in which A stands for a phenyl, Xstands for hydrogen, R¹ and R², independently of one another, stand forhydrogen, halogen, C₁-C₁₂-alkyl, C₁-C₁₂-alkoxy-C₁-C₁₀-alkylene,halo-C₁-C₁₀-alkyl, C₃-C₁₀-cycloalkyl or halo-C₃-C₁₀-cycloalkyl, and Ystands for a bond or for oxygen or for the group —S—, —S(O)— or —SO₂—,as well as isomers, enantiomers, diastereomers, and salts thereof. 5.Pharmaceutical agents that contain at least one compound according toclaim
 1. 6. Pharmaceutical agents according to claim 5 for use in thecase of tumor or metastasis growth, psoriasis, Kaposi's sarcoma,restenosis, such as, e.g., stent-induced restenosis, endometriosis,Crohn's disease, Hodgkin's disease, leukemia; arthritis, such asrheumatoid arthritis, hemangioma, angiofibroma; eye diseases, such asdiabetic retinopathy, neovascular glaucoma; renal diseases, such asglomerulonephritis, diabetic nephropathy, malignant nephroscferosis,thrombic microangiopathic syndrome, transplant rejections andglomerulopathy; fibrotic diseases, such,as cirrhosis of the liver,mesangial cell proliferative diseases, arteriosclerosis, injuries tonerve tissue, inhibition of the reocclusion of vessels after ballooncatheter treatment, vascular prosthetics or use of mechanical devices tokeep vessels open, such as, e.g., stents, and as immunosuppressiveagents, and for supporting scar-free healing, in senile keratosis and incontact dermatitis.
 7. Compounds according to claim 1 and correspondingpharmaceutical agents, with suitable formulation substances andvehicles.
 8. Use of the compounds of formula I, according to claim 1, asinhibitors of the tyrosine kinases KDR, FLT-1 and FLT-4.
 9. Use of thecompounds of general formula I, according to claim 1, in the form of apharmaceutical preparation for enteral, parenteral and oraladministration.
 10. Use of the compounds according to claim 1 in theinduced restenosis, endometriosis, Crohn's disease, Hodgkin's disease,leukemia; arthritis, such as rheumatoid arthritis, hemangioma,angiofibroma; eye diseases, such as diabetic retinopathy, neovascularglaucoma; renal diseases, such as glomerulonephritis, diabeticnephropathy, malignant nephrosclerosis, thrombic microangiopathicsyndrome, transplant rejections and glomerulopathy; fibrotic diseases,such as cirrhosis of the liver, mesangial cell proliferative diseases,arteriosclerosis, injuries to nerve tissue, and for inhibiting thereocclusion of vessels after balloon catheter treatment, in vascularprosthetics or after mechanical devices are used to keep vessels open,such as, e.g., stents, and as immunosuppressive agents, and forsupporting scar-free healing, and in senile keratosis and in contactdermatitis.
 11. Use of the compounds of general formula I, according toclaim 1, as VEGFR kinase 3 inhibitors of lymphangiogenesis.